Cohen Jessica I, Roychowdhury Sanjoy, DiBello Patricia M, Jacobsen Donald W, Nagy Laura E
Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA.
Hepatology. 2009 May;49(5):1709-17. doi: 10.1002/hep.22837.
Ethanol-induced liver injury is characterized by increased formation of reactive oxygen species (ROS) and inflammatory cytokines, resulting in the development of hepatic steatosis, injury, and cell death by necrosis and apoptosis. Thioredoxin (Trx), a potent antioxidant and antiinflammatory molecule with antiapoptotic properties, protects animals from a number of inflammatory diseases. However, the effects of ethanol on Trx or its role in ethanol-induced liver injury are not known. Female C57BL/6 mice were allowed ad libitum access to a Lieber-deCarli ethanol diet with 5.4% of calories as ethanol for 2 days to acclimate them to the diet, followed by 2 days with 32.4% of calories as ethanol or pair-fed control diet. Hepatic Trx-1 was decreased by ethanol feeding; daily supplementation with recombinant human Trx (rhTrx) prevented this ethanol-induced decrease. Therefore, we tested the hypothesis that administration of rhTrx during ethanol exposure would attenuate ethanol-induced oxidative stress, inflammatory cytokine production, and apoptosis. Mice were treated with a daily intraperitoneal injection of either 5 g/kg of rhTrx or phosphate-buffered saline (PBS).
Ethanol feeding increased accumulation of hepatic 4-hydroxynonenal protein adducts, expression of hepatic tumor necrosis factor alpha, and resulted in hepatic steatosis and increased plasma aspartate aminotransferase and alanine aminotransferase. In ethanol-fed mice, treatment with rhTrx reduced 4-hydroxynonenal adduct accumulation, inflammatory cytokine expression, decreased hepatic triglyceride, and improved liver enzyme profiles. Ethanol feeding also increased transferase-mediated dUTP-biotin nick-end labeling-positive cells, caspase-3 activity, and cytokeratin-18 staining in the liver. rhTrx treatment prevented these increases. In summary, rhTrx attenuated ethanol-induced increases in markers of oxidative stress, inflammatory cytokine expression, and apoptosis.
乙醇诱导的肝损伤的特征是活性氧（ROS）和炎性细胞因子生成增加，导致肝脂肪变性、损伤以及通过坏死和凋亡引起的细胞死亡。硫氧还蛋白（Trx）是一种具有抗凋亡特性的强效抗氧化和抗炎分子，可保护动物免受多种炎性疾病的侵害。然而，乙醇对Trx的影响或其在乙醇诱导的肝损伤中的作用尚不清楚。雌性C57BL/6小鼠随意进食含5.4%热量乙醇的Lieber-deCarli乙醇饮食2天，使其适应该饮食，随后2天给予含32.4%热量乙醇的饮食或配对喂养对照饮食。乙醇喂养使肝脏Trx-1减少；每日补充重组人Trx（rhTrx）可防止这种乙醇诱导的减少。因此，我们测试了以下假设：在乙醇暴露期间给予rhTrx会减轻乙醇诱导的氧化应激、炎性细胞因子产生和凋亡。小鼠每天腹腔注射5 g/kg的rhTrx或磷酸盐缓冲盐水（PBS）。
乙醇喂养增加了肝脏4-羟基壬烯醛蛋白加合物的积累、肝脏肿瘤坏死因子α的表达，并导致肝脂肪变性以及血浆天冬氨酸转氨酶和丙氨酸转氨酶升高。在乙醇喂养的小鼠中，rhTrx治疗减少了4-羟基壬烯醛加合物的积累、炎性细胞因子的表达，降低了肝脏甘油三酯水平，并改善了肝酶谱。乙醇喂养还增加了肝脏中转氨酶介导的dUTP-生物素缺口末端标记阳性细胞、半胱天冬酶-3活性和细胞角蛋白-18染色。rhTrx治疗可防止这些增加。总之，rhTrx减轻了乙醇诱导的氧化应激标志物、炎性细胞因子表达和凋亡的增加。
